The dilemma of artificial plasma replacement solutions resides in the fact that the chemical modification of biopolymers provides stable colloids soluble in blood on the one hand, but leaves colloid molecules in the body, which are stored in the organs, on the other. The infusion of hydroxyalkyl starch and carboxyalkyl starch solutions serves for the replacement of blood or its plasma components. The infused colloids are supposed to maintain the physiological colloid-osmotic pressure, which is essentially attributed to albumin. The vapor pressure lowering caused by the dispersed colloids promotes the influx of water from the interstitial tissue into the blood vessels. This effect plays an essential role, in particular, in septic patients, in whom significant displacements of water from the blood into the interstitial tissue occurs because of barrier disorders between the interstitial tissue and the blood. Further effects include the positive effect of the water retained in the blood vessels on the flow properties of the blood, and the promotion of laminar flows within the vessels. Hydroxyalkyl starches are usually prepared from potato or waxy maize starch. Being naturally grown polymer compounds, they have molecular weights and branching patterns that are very different from molecule to molecule. After hydrolytic cleavage into smaller and more unitary molecules that are distributed relatively closely around a defined average of the molecular weight, a defined amount of hydroxyalkyl groups is introduced into the colloid for improving the water solubility and for protection from enzymatic cleavage. Such modified starch preparations are characterized by two quantities, the molar substitution, MS, and the average molecular weight, Mw. The molar substitution MS corresponds to the total number of hydroxyethyl groups per the total number of glucose molecules. The molecular weight Mw corresponds to the weight average of all molecules of the polydisperse colloid mixture. The narrow molecular weight distribution around the average molecular weight is considered a quality criterion for the hydroxyethyl starch solutions approved as medicaments. The elimination of hydroxyalkyl and carboxyalkyl starch is believed to be primarily dependent on the molar substitution MS. The influence of the molar substitution on the elimination rate for hydroxyethyl starch is based on the steric hindrance of the enzymatic attack by hydrolytically acting enzymes. The higher the number of hydroxyethyl groups introduced into the starch molecule, the more slowly is the hydroxyethyl starch excreted. The infusion of hydroxyalkyl starches is quantitatively limited because of its being stored in the RHS (reticulohistiocytic system) and the impairment resulting therefrom, which is discussed very controversially. Since highly substituted colloids, above all, are phagocytosed and stored to a higher extent, the molar substitution of more recent HES solutions is clearly reduced. The hydrolytic degradation of hydroxyethyl starch in blood is mainly explained by the activity of α-amylase. The enzyme, a tetramer having a molecular weight of about 60 kDa, cleaves off glucose residues, maltose or maltotrioses from the terminal portions of hydroxyethyl starch. The cleavage of the 1,6-branching sites and the hydrolytic separation of longer residues are less frequent, depending on the degree of branching of the starting starch. After infusion, the proportion of C2-substituted hydroxyalkyl glucoses as compared to C6-substituted ones is clearly increased. With hydroxyethyl starch infusions in healthy subjects, Weitler and Sommermeier and Förster et al. made the following observations:
The width of the molecular weight distribution of hydroxyethyl starch present in blood decreases with time after the infusion. In the urine, the average molecular weight significantly increases with time. After infusion of a hydroxyethyl starch (HES) (e.g., Mw: 200 kDa; MS: 0.5), the molecular weight of the HES excreted in the urine increases (from 20 kDa to 40 kDa). No molecular weights above 70 kDa were found in the urine of healthy subjects. The substitution of the HES secreted in the urine increases to a similar extent that the molar substitution of the hydroxyethyl starch remaining in the serum increases.
It is assumed that these molecules are stored by the cells of the RHS as so-called residual starches. Now, while the serum half life of an HES sufficiently correlates with its degree of substitution, which suggests the steric hindrance of hydrolytic enzymes, especially serum amylase, by the introduced hydroxyalkyl groups, the course of the secreted molecular weight sizes in the urine remains obscure.
The replacement of intravasal liquid belongs to the most important measures in the prophylaxis and therapy of hypovolemia, irrespective of whether the hypovolemia results from the direct loss of blood or body fluids (in acute bleeding, traumas, surgery, burns), from distribution disorders between the macro- and microcirculation (as in sepsis), or from a vasodilation (e.g., in the induction of anaesthesia). Infusion solutions suitable for these indications are to restore normovolemia and to maintain the perfusion of vital organs and the peripheral blood flow. At the same time, the solutions must not exceedingly stress the circulation, and they must be substantially free of side effects. In this respect, all the volume replacement solutions available to date offer both advantages and disadvantages. While so-called crystalloid solutions (electrolyte solutions) are substantially free from direct side effects, they ensure only a short-term or inadequate stabilization of the intravasal volume and hemodynamics. In pronounced or longer lasting hypovolemia, they must be infused in excessive amounts, because they do not remain exclusively in the intravasal compartment, but are quickly distributed in the extravasal space. However, a rapid drainage into the extravasal space not only limits the volume-replacing effect of crystalloid solutions, but also bears the risk of peripheral and pulmonary edemas. Apart from the vital threat that a pulmonary edema may mean, it additionally leads to a deterioration of nutritive oxygen supply, which is also adversely affected by peripheral edemas.
In contrast, colloidal volume replacement solutions have a far more reliable effect, irrespective of whether the colloids contained therein are of natural or synthetic origin. This is due to the fact that their colloid-osmotic effect causes them to longer retain the supplied liquid in the circulation as compared to crystalloids, thus protecting them from being drained into the interstitium. On the other hand, colloidal volume replacement solutions give rise to undesirable reactions to a higher extent as compared to crystalloid solutions. Thus, the natural colloid albumin, like all blood and plasma derivatives, bears the risk of infection with viral diseases; in addition, interactions with other drugs, such as ACE inhibitors, may occur; finally, the availability of albumin is limited, and its use as a volume replacement is disproportionately expensive. Further doubts as to the use of albumin as a volume replacement are due to the inhibition of the endogenous synthesis of albumin if it is added exogenously and due to its ready extravascularization. This means the passage from the circulation into the extravascular space, where undesirable and persistant liquid accumulations can occur because of the colloid-osmotic effect of albumin.
In the synthetic colloids, severe anaphylactoid responses and a massive inhibition of blood coagulation have caused dextran preparations to disappear almost completely from therapy. Although hydroxyethyl starch (HES) solutions also have the potential for triggering anaphylactoid responses and affecting blood coagulation, this is to a lesser extent as compared with dextran. Severe anaphylactoid responses (responses of severity III and IV) are observed extremely rarely with HES solutions, in contrast to dextran, and the influence on blood coagulation, inherent to the high-molecular weight HES solutions, could be significantly reduced in recent years by the further development of HES solutions. As compared with gelatin solutions, which also find use as plasma replacements and leave blood coagulation essentially unaffected, HES solutions, at least their high- and medium-molecular weight embodiments, have the benefit of a longer plasma residence time and effectiveness.
EP-A-0 402 724 discloses the preparation and use of a hydroxyethyl starch having an average molecular weight, Mw, of from 60,000 to 600,000, a molar substitution, MS, of from 0.15 to 0.5, and a degree of substitution, DS, of from 0.15 to 0.5. The disclosure deals with the rapid (6 to 12 hours) and complete degradability of the hydroxyethyl starches to be employed as plasma expanders. Within the preferred range of average molecular weights of from 100,000 to 300,000, a hydroxyethyl starch having an average molecular weight of 234,000 was explicitly examined.
U.S. Pat. No. 5,502,043 discloses the use of hydroxyethyl starches having an average molecular weight, Mw, of from 110,000 to 150,000, a molar substitution, MS, of from 0.38 to 0.5, and a degree of substitution, DS, of from 0.32 to 0.45 for improving microcirculation in peripheral arterial occlusive disease. In addition, the document teaches the use of low-molecular weight (Mw 110,000 to 150,000) hydroxyethyl starches which, due to their low molecular weight, keep the plasma viscosity low and thus ensure an improvement of microcirculation in the blood flow. However, this document advises against the use of higher-molecular weight hydroxyethyl starches, such as a hydroxyethyl starch with an Mw of 500,000, because they increase plasma viscosity and thus deteriorate microcirculation despite their low molar substitution (MS=0.28).
Worldwide, different HES preparations are currently used as colloidal volume replacements, which are mainly distinguished by their molecular weights and additionally by their extent of etherification with hydroxyethyl groups, and by other parameters. The best known representatives of this class of substances are the so-called Hetastarch (HES 450/0.7) and Pentastarch (HES 200/0.5). The latter is the currently most widespread “standard HES”. Besides, HES 200/0.62 and HES 70/0.5 play a minor role. The declared information relating to the molecular weight as well as that relating to the other parameters are averaged quantities, where the molecular weight declaration is based on the weight average (Mw) expressed in daltons (e.g., for HES 200,000) or mostly abbreviated in kilodaltons (e.g., for HES 200). The extent of etherification with hydroxyethyl groups is characterized by the molar substitution MS (e.g. as 0.5 such as in HES 200/0.5; MS=average molar ratio of hydroxyethyl groups to anhydroglucose units) or by the degree of substitution (DS=ratio of mono- or polyhydroxyethylated glucoses to the total anhydroglucose units). According to their molecular weights, the HES solutions in clinical use are classified into high-molecular weight (450 kD), medium-molecular weight (200-250 kD) and low-molecular weight (70-130 kD) preparations.
As to the coagulation effects of HES solutions, a distinction is to be made between non-specific and specific influences. A non-specific influence on blood coagulation results from dilution of the blood (hemodilution), which occurs during the infusion of HES solutions and other volume replacements into the circulation. Affected by this hemodilution are also coagulation factors, whose concentrations are decreased depending on the extent and duration of the dilution of the blood and the plasma proteins due to the infusion. Correspondingly large or persisting effects may result in a hypocoagulability which is detectable by laboratory diagnostics and, in extreme cases, clinically relevant.
In addition, hydroxyethyl starch may cause a specific influence on blood coagulation, for which several factors are held responsible. Thus, under certain conditions or with certain HES preparations, a decrease of the coagulation proteins factor VIII (F VIII) and von Willebrand factor (vWF) is found which is larger than the general decrease of the plasma proteins due to hemodilution. Whether this larger than expected decrease is caused by a reduced formation or release of F VIII/vWF, such as by coating effects on the vascular endothelium caused by HES, or by other mechanisms is not quite clear.
However, HES influences not only the concentration of the coagulation factors mentioned but evidently also the function of platelets. This is completely or in part due to the binding of HES to the surface of the platelets, which inhibits the access of ligands to the fibrinogen receptor of the platelets.
These specific effects of HES on blood coagulation are particularly pronounced when high-molecular weight HES (e.g., HES 450/0.7) are employed while they do not play such a great role for medium-molecular weight (e.g., HES 250/0.5) or low-molecular weight HES (e.g., HES130/0.4 or HES 70/0.5) (J. Treib et al., Intensive Care Med. (1999), pp. 258 to 268; O. Langeron et al., Anesth. Analg. (2001), pp. 855 to 862; R. G. Strauss et al., Transfusion (1988), pp. 257-260; M. Jamnicki et al., Anesthesiology (2000), pp. 1231 to 1237).
If the risk profile of high-molecular weight HES is compared with that of the medium- and low-molecular weight preparations, a clear reduction of the risks can be established in the latter, i.e., not only with respect to the interaction with blood coagulation but also with respect to particular pharmacokinetic properties. Thus, the high-molecular weight HES solutions show a high accumulation in the circulation while this drawback is reduced in medium-molecular weight HES and virtually absent in low-molecular weight preparations. The fact that no more accumulation occurs with low-molecular weight HES solutions, such as HES130/0.4, is a relevant therapeutic progress because the plasma levels of HES cannot be determined in clinical routine, and therefore, even extreme concentrations, which can be obtained within a few days with the high-molecular weight solutions, remain undiscovered. In this case, the amount of “residual HES” accumulated in the circulation is unknown to the user but it nevertheless influences the kinetics and behavior of the HES which was additively infused, not knowing the amounts still present in the circulation. Therefore, the effect of high-molecular weight HES according to the prior art is not calculable; it remains longer in the circulation than would be required or desired for therapeutic reasons in most cases, and its metabolic fate is unclear.
In contrast, low-molecular weight HES will disappear completely from the circulation within about 20 to 24 hours after the infusion. This avoids backlog effects, and no accumulation occurs, especially for repeated infusions. The pharmacokinetic behavior of low-molecular weight starch, in contrast to high-molecular weight starch, is calculable and therefore can be easily controlled. Too high a load on the circulation or the clearance mechanisms does not occur.
However, this behavior of low-molecular weight HES as compared to high-molecular weight preparations, which is advantageous as such, is purchased at the expense of a significantly shorter plasma half life. The plasma half life of low-molecular weight HES is only about half that of HES 200 or less (3. Waitzinger et al., Clin. Drug Invest. (1998), pp. 151 to 160) and is in the range of the half life of gelatin preparations, which are to be rated as decidedly short-term effective. Although a short half life of a volume replacement need not be categorically disadvantageous, because it can be compensated for by a more frequent or more highly dosed administration of the volume replacement in question, in severe or persisting hypovolemia, a volume replacement with a short half life and short effective period involves the risk of insufficient circulation filling (much like with crystalloid solutions) or, when the dosage is correspondingly increased for compensating for this drawback, the risk of interstitial liquid overload.
Before this background, there is a need for a volume replacement which on the one hand is characterized by a low tendency to accumulation and a low influence on blood coagulation (such as low-molecular weight HES) but on the other hand has a longer half life as compared to the low-molecular weight HES solutions, whose properties are close to those of crystalloid solutions.